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Review
. 2022 Feb 10;23(4):1963.
doi: 10.3390/ijms23041963.

Physiology and Pathophysiology of Heparan Sulfate in Animal Models: Its Biosynthesis and Degradation

Ryuichi Mashima  1 , Torayuki Okuyama  1 , Mari Ohira  1
Affiliations
Review

Physiology and Pathophysiology of Heparan Sulfate in Animal Models: Its Biosynthesis and Degradation

Ryuichi Mashima et al. Int J Mol Sci. .

Abstract

Heparan sulfate (HS) is a type of glycosaminoglycan that plays a key role in a variety of biological functions in neurology, skeletal development, immunology, and tumor metastasis. Biosynthesis of HS is initiated by a link of xylose to Ser residue of HS proteoglycans, followed by the formation of a linker tetrasaccharide. Then, an extension reaction of HS disaccharide occurs through polymerization of many repetitive units consisting of iduronic acid and N-acetylglucosamine. Subsequently, several modification reactions take place to complete the maturation of HS. The sulfation positions of N-, 2-O-, 6-O-, and 3-O- are all mediated by specific enzymes that may have multiple isozymes. C5-epimerization is facilitated by the epimerase enzyme that converts glucuronic acid to iduronic acid. Once these enzymatic reactions have been completed, the desulfation reaction further modifies HS. Apart from HS biosynthesis, the degradation of HS is largely mediated by the lysosome, an intracellular organelle with acidic pH. Mucopolysaccharidosis is a genetic disorder characterized by an accumulation of glycosaminoglycans in the body associated with neuronal, skeletal, and visceral disorders. Genetically modified animal models have significantly contributed to the understanding of the in vivo role of these enzymes. Their role and potential link to diseases are also discussed.

Keywords: biosynthesis; heparan sulfate; knockout mice; lysosome.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
HS biosynthesis. (A) Extension of HS from proteoglycan. (B) Enzyme reaction of modification in HS. Note that SULF1 and SULF2 are involved in the removal of 6-O-sulfate in the last 2 steps. (C) Chemical structure of ΔUA-GlcNAc.
Figure 2
Figure 2
Degradation of HS by lysosomal enzymes involved in mucopolysaccharidosis. Enzymes involved in MPS disease subtypes are as follows: MPS I, α-l-iduronidase; MPS II, iduronate 2-sulfatase; MPS IIIA, heparan N-sulfatase; MPS IIIB, α-N-acetylglucosaminidase; MPS IIIC, acetyl CoA: α-glucosaminide acetyltransferase; MPS IIID, N-acetylglucosamine 6-sulfatase; MPS VII, β-glucuronidase.
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